The candidate for this K23 award is dedicated to becoming an independent patient-oriented investigator with expertise in biomarker development and evaluation, clinical trials, and mineralocorticoid-induced hypertension. The proposed award will allow the candidate to accomplish this goal while evaluating a novel biomarker of mineralocorticoid receptor (MR) activation for use in tailored antihypertensive therapy. Candidate. The candidate is well prepared for this award because of his prior training. After internal medicine residency, he investigated the pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-associated angioedema in Vanderbilt University's Division of Clinical Pharmacology. While receiving excellent training in the clinical management of hypertension, he enrolled study participants and assayed their samples in the laboratory, igniting a passion for patient-oriented research. He earned Vanderbilt's Master of Science in Clinical Investigation degree. In addition, he helped conduct a randomized trial to treat acute ACEi-associated angioedema while developing an animal model recapitulating important aspects of this rare, but potentially fatal problem. Based upon a growing interest in hypertension and cardiovascular disease, he completed a clinical cardiovascular medicine fellowship at the University of Colorado, where he was elected the Gilbert Blount Endowed Research Fellow. During this fellowship, he maintained a research focus on hypertension. Upon recruitment to the University of Michigan, he has turned his attention to a problem of major public health importance: tailored treatment of patients with hypertension. The candidate is a cardiologist, and American Society of Hypertension-Certified Hypertension Specialist. He is well positioned to become a leader in patient-oriented hypertension research. His background in patient- oriented research has prepared him to become an expert in the clinical investigation of mineralocorticoid-induced hypertension. His research independence will be achieved through three Training Objectives: (1) comprehensive laboratory and statistical training relevant to biomarkers of human MR activation, (2) in-depth training in endocrine hypertension and aldosterone's effects on human physiology, and (3) experience directing a randomized controlled trial (RCT). Environment. The proposed research and training will take place at the University of Michigan, which has a proud legacy of seminal mineralocorticoid research. The candidate is a faculty member in Cardiovascular Medicine, which has close collaborative ties with the Division of Metabolism, Endocrinology, and Diabetes; the Department of Physiology; and the University of Michigan's CTSA, the Michigan Institute for Clinical and Health Research. The proposed work will be completed under close mentorship from Drs. Richard Auchus, MD, PhD and William Rainey, PhD, recognized experts in mineralocorticoid biology, both of whom have mentored K awardees. Robert Brook, MD will guide the candidate in the contemporary conduct of hypertension RCTs. Muneesh Tewari, MD, PhD will train the PI in transcriptomics, completing the mentorship team. Research. The focus of this K23 proposal is hypertension, a condition affecting 33% of the United States' adult population. Hypertension increases the risk of cardiovascular disease and death, and its treatment reduces these risks. Hypertension resistant to treatment is common. Approximately 20% of patients with resistant hypertension have primary aldosteronism, in which inappropriate aldosterone secretion leads to activation of MR. Activation of MR increases the expression of serum/glucocorticoid regulated kinase 1 (SGK1), glucocorticoid-induced leucine zipper, and the amiloride-sensitive epithelial sodium channel (ENaC) in the distal nephron, resulting in sodium and water retention. MR antagonists (MRAs) are predictably effective in the treatment of primary aldosteronism. Beyond primary aldosteronism, MRAs are also an effective antihypertensive treatment in many patients with normal or low circulating levels of aldosterone. However, an uncertain risk-benefit ratio has precluded common use of MRAs for hypertension. No biomarker of MR activation exists, but such a biomarker would permit clinicians to target MRA therapy to appropriate patients and spare other patients unnecessary adverse effects. Preliminary data suggest that mRNA encoding MR-regulated genes is quantifiable in urinary exosomes, 40-120 nm microvesicles shed by cells. The overall scientific objective of this proposal is to evaluate whether mRNA shuttled by urinary exosomes is a clinically useful biomarker of MR activation. Specific Aim 1 (aligns with Training Objective 1): Define biomarkers of MR activation in urinary exosomes in healthy volunteers on high- and low-sodium diet a. Determine the utility of known MR-responsive genes as biomarkers in urinary exosomes b. Use transcriptome analysis to define novel biomarkers of mineralocorticoid excess in urinary exosomes Specific Aim 2 (aligns with Training Objective 2): Determine the utility of MR-responsive transcript abundance in urinary exosome-shuttled for the diagnosis and subtyping of primary aldosteronism Specific Aim 3 (aligns with Training Objective 3): Evaluate urinary exosome-shuttled MR-responsive transcript patterns as predictors of blood pressure response to spironolactone in patients with low-renin hypertension Summary. The proposed K23 award will provide the candidate sufficient protected time and training to become an independent clinical translational hypertension investigator. The research will answer important, tractable questions about exosome-shuttle transcriptional biomarkers for tailoring antihypertensive therapy.